痛覚、痒み、その障害 Pain, Itch and Their Disorders
O2-7-1-1 ミクログリアP2X4受容体の発現増加および神経障害性疼痛におけるIRF5の役割 Role of IRF5 in P2X4R upregulation in microglia and neuropathic pain ○津田誠1, 増田隆博1, 岩本祥佑1, 齊藤秀俊1, 田村智彦2, 井上和秀1 ○Makoto Tsuda1, Takahiro Masuda1, Shosuke Iwamoto1, Hidetoshi Tozaki-Saitoh1, Tomohiko Tamura2, Kazuhide Inoue1 九州大学大学院 薬学研究院 薬理学1, 横浜市立大学大学院　医学研究科　免疫学2 Dept. Mol. Syst. Pharmacol., Grad. Sch. Pharm. Sci., Kyushu Univ., Fukuoka, Japan1, Dept. Immunol., Grad. Sch. Med., Yokohama City Univ., Yokohama, Japan2 Neuropathic pain, a debilitating chronic pain condition, is a common consequence of damage to the nervous system. Optimally treating neuropathic pain is a major clinical challenge. Emerging lines of evidence indicate that peripheral nerve injury (PNI) converts spinal microglia into reactive cells that are required for the development and maintenance of neuropathic pain. We have previously shown that the transcription factor interferon regulatory factor-8 (IRF8) is upregulated in spinal microglia after PNI and regulates expression of genes crucial for converting the cells to reactive ones. Here we identify IRF5 as a target of IRF8 and as being required for upregulation of P2X4 receptors (P2X4Rs; an ATP-gated channel essential for producing neuropathic pain). We found that PNI increased expression of IRF5 in spinal microglia in a cell type-specific manner. The upregulation of IRF5 expression was abolished in IRF8-deficient mice. Interestingly, IRF8-induced upregulation of P2X4Rs in cultured microglia was suppressed by knockdown of IRF5 expression. Furthermore, knockdown of IRF5 by spinal administration of IRF5 siRNA attenuated pain hypersensitivity after PNI. Thus, our present findings indicate that the IRF8-mediated IRF5 expression is required for converting to P2X4R-positive microglia that drive neuropathic pain.	O2-7-1-2 MicroPETを用いた急性および慢性疼痛モデルラットにおける疼痛認知・伝達回路の解析 Neuroimaging analysis using small-animal PET of the pain matrix in acute and chronic pain model rats ○崔翼龍1, 佐古健生1, 豊田浩士2, 林中恵美2, 和田康弘2, 渡辺恭良2, 片岡洋祐1 ○Yilong Cui1, Takeo Sako1, Hiroshi Toyoda2, Emi Hayashinaka2, Yasuhiro Wada2, Yasuyoshi Watanabe2, Yosky Kataoka1 理化学研究所・分子イメージング科学研究センター・細胞機能イメージング研究チーム1, 理化学研究所・分子イメージング科学研究センター・分子プローブ動態応用研究チーム2 Cellular Function Imaging Laboratory, RIKEN Center for Molecular Imaging Science1, Molecular Probe Dynamics Laboratory, RIKEN Center for Molecular Imaging Science2 Pain is an unpleasant subjective sensation associated with actual or potential tissue damage, and is usually modified by personal memories, emotion, and cognition. Recent neuroimaging studies in human demonstrated that the nociceptive processing involves widely-distributed brain networks, including the somatosensory, insular, cingulate, and prefrontal cortices, and the thalamus. Recently, we have developed a small-animal neuroimaging method combining 2-[18F]fluoro-2-deoxy-D-glucose (FDG) PET imaging with statistical parametric mapping (SPM) analysis to evaluate regional brain activity in the rodent central nervous system. In order to investigate whether the nociceptive pathways in chronic pain overlap with physiological "pain matrix" or not, we compared the evoked regional brain activity induced by noxious mechanical stimuli applied to the affected hind paw, in the neuropathic pain model rats and sham-operated rats. In the chronic neuropathic pain model, the regional brain activity was significantly increased in the primary somatosensory cortex hind limb area, primary motor cortex, centrolateral thalamic nucleus, and posterior thalamic nucleus in response to mechanical stimuli. In the sham-operated rats, the regional brain activity was increased in the primary somatosensory and motor cortices, anterior cingulate cortex, and dorsomedial stratum. The posterior cingulate cortex was significantly activated by acute noxious mechanical stimuli in sham-operated rats, but not in the chronic neuropathic pain model rats. These results indicate that the nociceptive pathways in chronic neuropathic pain may be different from the physiological "pain matrix" associated with acute mechanical pain.
O2-7-1-3 オキサリプラチン誘発性の末梢神経障害急性期におけるROSを介したTRPA1の関与 Involvement of ROS-mediated TRPA1 activation in oxaliplatin-induced acute peripheral neuropathy ○趙萌1, 三宅崇仁1, 中村彩希1, 浜野智2, 高橋重成2, 白川久志1, 中川貴之1, 森泰生2, 金子周司1 ○Meng Zhao1, Takahito Miyake1, Saki Nakamura1, Satoshi Hamano2, Nobuaki Takahashi2, Hisashi Shirakawa1, Takayuki Nakagawa1, Yasuo Mori2, Shuji Kaneko1 京都大院・薬・生体機能解析1, 京都大院・工・合成・生物化学専攻・分子生物化学2 Dept. Mol. Pharmacol., Grad. Sch. Pharmaceu. Sci., Kyoto Univ., Kyoto, Japan1, Dept. Synth. Chem. and Biol. Chem., Grad. Sch. of Engineer., Kyoto Univ., Kyoto, Japan2 Oxaliplatin, a platinum-based chemotherapeutic agent, causes peculiar acute peripheral neuropathy, which appears in almost all patients rapidly after infusion and is triggered or exacerbated by cold. Recently, we reported that acute cold hypersensitivity induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice (Mol Pain 2012). In this study, we further explored the mechanisms how TRPA1 is activated and/or sensitized by oxaliplatin. In Calcium imaging and patch-clamp tests using HEK293 cells expressing recombinant human TRPA1, high doses of oxaliplatin (100-1000 μM) evoked a calcium response and increased whole-cell currents, respectively, but not in mock-transfected cells. Furthermore, single-channel currents were increased by oxaliplatin applied from the intracellular side of cell-free, excised inside-out patches, suggesting that oxaliplatin can activate TRPA1 directly. On the other hand, when mouse cultured DRG neurons were pretreated with oxaliplatin (100 μM) for 2 h, the number of AITC-sensitive neurons was significantly increased, suggesting that treatment with relatively low concentrations of oxaliplatin for several hours can induce sensitization of TRPA1. ROS is involved in oxaliplatin-induced neuropathy and TRPA1 has sensitivity for ROS. In HEK293 cells preloaded with H2O2-specific indicator PG1, oxaliplatin increased H2O2 production. Furthermore, in TRPA1-expressing cells pretreated with oxaliplatin (100 μM) for 2 h, H2O2 (200 μM) increased whole-cell currents, while no current was detected in vehicle-pretreated cells. Finally, nocifensive behaviors evoked by i.pl. injection of H2O2 were significantly enhanced 2 h after oxaliplatin administration. Taken together, these results suggest that oxaliplatin leads to TRPA1 sensitization, although it has an ability to activate TRPA1 directly. Subsequently, ROS produced by oxaliplatin can activate sensitized TRPA1, which may contribute to the oxaliplatin-induced acute peripheral neuropathy.	O2-7-1-4 Intra- paragigantocellularis lateralis injection of orexin-A has an antinociceptive effect on hot plate and formalin tests in rat ○Hassan Azhdari Zarmehri1,2, Elaheh Erami3 Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran,1, Department of Physiology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran2 Systemic injection of ORXA (hypocretin-1) has been shown to elicit analgesic responses processes and OX1R is involved in responsiveness to both pain and stressful stimuli. However, the locations of central sites that may mediate these effects have not been clearly elucidated. In the present study, the effect of orexin-A (ORXA) microinjection into the paragigantocellularis lateralis (LPGI) on nociceptive behaviors, using hot-plate and formalin tests as thermal and chemical models of pain in rat, was examined. Also, we determined whether the pretreatment with SB-334867, a selective OX1-receptor antagonist, would prevent the antinociceptive effect of orexin-A. ORXA microinjected into the LPGi nucleus, dose-dependently decreased the formalin induced nociceptive behaviors and also produced a dose-dependent antinociceptive effect in the hot-plate test. Pretreatment with a selective orexin receptor 1 (OX1R) antagonist, SB-334867, also inhibited the effect of ORXA on formalin induced nociceptive behaviors while the SB-334867 alone had no effect on formalin test. These data demonstrated that the ORXA-induced antinociception in formalin test is mainly mediated through the OX1R in LPGi which might play a potential role in processing the pain information associated with descending pain modulation.

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